Project Summary/Abstract The Center for Innovative Visual Rehabilitation (CIVR) was founded at the Boston VA hospital in 2001 as an outgrowth of the Boston Retinal Implant Project, which had been a multi-disciplinary collaboration between the Harvard Medical School/ Massachusetts Eye and Ear Infirmary and the Massachusetts Institute of Technology since the late 1980s. The goal of the CIVR is to develop advanced technologies to create new therapies to restore vision to veterans who are blind from retinal disease. More specifically, the goal of the CIVR is the creation of a micro-electronic implant to restore vision to veterans who have retinal disease that is not treatable. The most significant blinding condition of this type is age-related macular degeneration (AMD), which is the leading cause of blindness among veterans. Our device might also be able to help some of the roughly 8,000 veterans who have retinitis pigmentosa, which causes more severe and diffuse blindness than AMD. Our prosthesis could also potentially be relevant to veterans who develop retinal damage from battlefield injuries. The CIVR has successfully built and testing a wireless retinal prosthesis that has functioned as designed for up to one year in pig eye. Our group has recently initiated communication with the FDA to seek an Investigational Device Exemption (IDE) to enable performance of long-term human implants. We are currently in the process of upgrading our laboratory device that has been used in animal experiments to make it suitable for human use. Two large problems stand in the way of successfully restoring vision to blind veterans: 1) the tendency for electrical stimulation thresholds to be very high, which raises a concern about the safety of long-term stimulation; and 2) the lack of demonstration of high-quality visual percepts from the groups that have performed chronic human implants. Both problems can likely be solved by use of penetrating, rather than flat, electrodes. All groups worldwide, including our own, have been using flat electrodes for their retinal prosthetic devices. This proposal focuses on the design, creation and surgical implantation of three dimensional, penetrating electrodes that will be made on a flexible substrate. To accomplish these aims, the proposal describes use of advanced and customized microfabrication techniques to create the arrays, and a variety of in vitro and in vivo methods to study the electrical and physical integrity of the electrodes before, during and after implantation of these devices into the sub-retinal space of Yucatan mini-pigs. Additional studies will be made of the biocompatibility of the implanted electrode arrays, primary by histological examination of the eyes months after implantation. The results of this proposal have the potential to yield an improved electrode array that will enhance our plans for upgrading our human-quality prosthesis that is under development. A new electrode array could be easily incorporated into our prosthesis because we have developed a modular and reconfigurable design concept that allows us to introduce new components without requiring any change in the basic design or manufacture of our system.